Studies in cardiac surgical patients have shown an association of hyperglycemia with increased incidences of sepsis, mediastinitis, prolonged mechanical ventilation, cardiac arrhythmias and longer intensive care and hospital stay. There is considerable controversy regarding appropriate glycemic management in these patients and in the definition of hyperglycemia and hypoglycemia or the blood sugar levels at which therapy should be initiated. There is also dilemma regarding the usage of "tight glycemic control" with studies showing conflicting evidences. Part of the controversy can be explained by the differing designs of these studies and the variable definitions of hyperglycemia and hypoglycemia.

Ever since the Van den Berghe et al. [1] challenged the wisdom of tolerating "diabetes of injury", the literature has been flooded with basic and clinical research to address the merits of treating hyperglycemia in critically ill-patients. Many studies have focused on cardiac surgical patients and drawn similar conclusions. [2],[3] However, equally contradictory or equivocal [4],[5],[6],[7] inferences have left the question of aggressive glycemic control in the critically ill-patients, cardiac surgical subset included, to remain unanswered. The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial, [8] which was specifically designed to answer whether glycemic control will benefit the critically ill-patients, can it be achieved safely and reproducibly and, if so, at what premium have not provided definitive answers and the debate is yet to be settled. Multiple issues are involved in the policy of glycemic control. What is known is that a direct link exists between hyperglycemia and unfavorable convalescence; but if this metabolic perturbation is merely an epiphenomenon is not known. Even less definite is evidence that whether aggressive attempts to keep blood sugar level to normal fasting level is necessarily more rewarding than restricting the rise in blood sugar to an intermediate range of "permissive hyperglycemia" of around 150 mg/dl (8.33 mmol/l). In the pediatric cardiac surgical population, the evidence for the benefit of tight glycemic control (TGC) is insufficient and the dilemma is further compounded by the fact that even the definition of hyperglycemia and hypoglycemia is not settled. [9],[10],[11] In this article, we review the literature pertaining to blood glucose (BG) management in the critically ill-patients and explore the evidence and rationale behind the current practice of glycemic control.

Why worry about glucose at all? The rationale

Morbidity and mortality

Multiple studies demonstrate increased morbidity and mortality in association with the level and the duration of hyperglycemia. [12],[13],[14],[15],[16],[17],[18] The definition for hyperglycemia in most studies ranged from 144 to 270 mg/dl (8-15 mmol/l). This negative impact on outcome is influenced by not just the peak BG concentration but by the duration of hyperglycemia as well [15],[16] (72 h or more in the post-operative period). Additionally, a myriad of morbidity indicators have been causally linked with hyperglycemia including a prolonged need for mechanical ventilation, and increased length of intensive care unit (ICU) and hospital stay. [19],[20],[21] In addition, hyperglycemia is associated with an increased risk of infection due to altered leukocyte function, increased pathogen virulence and glycation of immunoglobulins. [22][Table 1] shows various complications of hyperglycemia in cardiac surgery patients.

In a couple of studies, 24 h peak BG level >130 mg/dl (7.22 mmol/l) was found to be a predictor for mediastinitis. [23],[24] Up to 86% children in pediatric ICU have hyperglycemia at some point during stay. Yates et al. [15] in a study including patients of <1 year requiring cardiopulmonary bypass (CPB) for repair and palliation of congenital cardiac defects, demonstrated that peak post-operative glucose concentration and duration of hyperglycemia was associated with increased morbidity and mortality. They considered hyperglycemia as random blood sugar (RBS) level >126 mg/dl (6.99 mmol/l) based on 2006 American Diabetes Association definition. [25] Falcao et al. [16] stratified severity of hyperglycemia into moderate (160-200 mg%; 8.88-11.1 mmol/l) and severe (>200 mg/dl; 11.1 mmol/l) arbitrarily based on a value of 20 mg/dl (1.11 mmol/l) above and below renal threshold. Duration of hyperglycemia was defined as the number of days with at least one RBS value of 126 mg/dl (6.99 mmol/l) or higher. Studies have demonstrated an association of hyperglycemia with longer stay in the hospital. [9],[17],[26] However, the link remains speculative in the absence of a well-designed randomized control trial of strict glycemic control. Hyperglycemia is found to be associated with increased risk of cardiac arrhythmias, and with impairment of ischemic preconditioning and development of collateral circulation following myocardial infarction. [10],[27]

Neurological issues

Hyperglycemia has been shown to be associated with cerebral edema formation and disruption of blood-brain barrier. [28] There are evidences implicating hyperglycemia in worsening outcome after brain injury in adults [29] as well as children. [30],[31] However, the Boston Circulatory Arrest Study that sought to investigate the impact of intraoperative hyperglycemia on neurodevelopmental outcomes after infant cardiac surgery failed to find such a correlation. [32] In a secondary analysis, effects of post-operative glucose levels in infants younger than 6 months of age undergoing repair of two-ventricle cardiac defects, the neurodevelopmental outcomes at 1 year were not associated with lower mental developmental index (MDI) and psychomotor developmental index (PDI) scores. [33] In a subsequent study from the same center, it was reported that hyperglycemia following Stage I palliation in the neonatal period was not associated with lower MDI or PDI scores at 1 year of age. [34]

Pathophysiology of hyperglycemia

The "stress hyperglycemia" or "diabetes of injury", insulin resistance, glucose intolerance and hyperglycemia, until recently, was interpreted as an adaptive stress response. BG concentrations of 160-200 mg/dl (8.88-11.1 mmol/l) were accepted to maximize cellular glucose uptake and sugar elevations were often not treated until levels exceeded renal threshold, 220 mg/dl (12.2 mmol/l) and glycosuria occurred. [35],[36] The flux of scientific research has changed this perception and the defining threshold for stress diabetes has been decreased to 110 mg/dl (6.11 mmol/l) from 180 mg/dl (9.99 mmol/l) in any critically ill-patient. [37] The major reason for this change in perception is the knowledge that strict hyperglycemia control is associated with better outcomes in terms of morbidity and mortality in cardiac surgical patients. Hyperglycemia occurs commonly in critically ill post-operative patients because of elevated hepatic glucose production, release of counter regulatory hormones, peripheral insulin resistance and response to administered steroids, catecholamines and fluid management. [38] Hyperglycemia causes direct cellular toxicity as well as through increased production of reactive oxygen species such as peroxynitrite and superoxide. Several other mechanisms for this association during critical illness have been proposed, including increased inflammatory cytokine production, acute dyslipidemia, endothelial dysfunction and hypercoagulation leading to metabolic disturbances and increased cellular apoptosis. [38] In the setting of insulin resistance and hyperglycemia, end organs that exhibit glucose-uptake without facilitation of insulin are particularly vulnerable. The central and peripheral nervous system, hepatocytes and endothelial, epithelial and immune cells represent these cellular compartments. [38] Under physiological circumstances, hyperglycemia down regulates glucose transporters thereby protecting these cells against glucose overload; however, in critical illness, the neurohormonal stress response overrules the normal protection of cells against hyperglycemia thus allowing cellular glucose overload in all organ systems that take up glucose passively. [38],[39] Intracellular hyperglycemia provokes increased mitochondrial production of reactive oxygen species and, to add to the insult, due to critical illness per se more reactive species may be generated due to cytokine-induced and hypoxia/reperfusion-associated superoxide production. Hence, when cells of critically ill-patients are overloaded with glucose, various pathophysiologic derangements are to be expected leading to end-organ injury, prolonged mechanical ventilation and sepsis. [38]

Pathophysiology of hypoglycemia

RBS value of 60-70 mg/dl (3.3-3.9 mmol/l) is cited as the lower limit of normal glucose though symptoms do not occur until 50-54 mg/dl (2.8-3 mmol/l). [40] Brain metabolism depends on continuous glucose supply, though a limited amount of glucose can be derived from glycogen stored in astrocytes (consumed in minutes). Brain is one of the first organs affected by hypoglycemia. RBS below 65 mg/dl (3.61 mmol/l) causes subtle reduction of mental efficiency in most people. Impairment of action and judgment is seen with RBS <40 mg/dl (2.22 mmol/l). Seizures occur as glucose falls further. At RBS <10 mg/dl (0.56 mmol/l), most neurons become electrically silent and non-functional resulting in coma (neuroglycopenia). If RBS levels fall too low, liver converts glycogen to glucose to tide over the crisis for a short while.

Effects of CPB

CPB is associated with surgical stress and release of gluconeogenic catecholamines that result in glycogenolysis, gluconeogenesis and hyperglycemia. This is associated with adverse outcomes such as neurological impairment, cardiac dysfunction, prolonged hospitalization and increased mortality. [41] Landymore et al. [42] studied pancreatic endocrine function and peripheral glucose utilization in 11 non-diabetic patients undergoing myocardial revascularization under CPB. They reported an increase in circulating insulin concentration with a mean of 216 μu/ml (1549.8 pmol/l) during CPB. The high circulating concentration of insulin returned to normal post-operatively in the recovery room. While surgical stress results in hyperglycemia, it has been suggested that CPB is the dominating contributor in cardiac surgery. Glucose homeostasis is disturbed pre-operatively for many non-diabetic patients undergoing CPB. CPB exacerbates the catabolism and the glucose homeostasis is disturbed to a lesser degree in surgeries performed without CPB. [40]

Toward glycemic control: What is the evidence?

The most perplexing aspect of glycemic control pertains to the widely divergent values used as cut-off to define a glycemic level. For example, in adults, hyperglycemia has been defined as a BG level exceeding 99 mg/dl (5.5 mmol/l) as well as one above 140 mg/dl (7.8 mmol/l). Similarly, in the pediatric population, the values of hyperglycemia defined are 110 mg/dl (6.11 mmol/l); 126 mg/dl (6.99 mmol/l); 150 mg/dl (8.33 mmol/l); and 200 mg/dl (11.1 mmol/l). [10],[43] The hypoglycemic threshold has been defined as BG level of <70 mg/dl (3.9 mmol/l), 40 mg/dl (2.2 mmol/l) or 50 mg/dl (2.8 mmol/l). This diversity indicates that there is no clear-cut agreement between cut off values. It is known that at a BG level below 60 mg/dl (3.33 mmol/l), counter-regulatory hormones are triggered and neurocognitive dysfunction can occur. Whereas observational studies have revealed a J-curved relationship between BG level and the risk of mortality, with a nadir roughly between 90 and 140 mg/dl (5-8 mmol/l), it is not clearly proven whether glycemia serves as a mediator of these outcomes or merely as a marker of a stress response to illness. That is, whether acute hyperglycemia per se leads to poor clinical outcomes or is it a reflection of sicker patients where increased counter regulatory forces manifest stress as hyperglycemia. [44] The Portland Diabetic Project, a non-randomized prospective study was one of the earliest studies to demonstrate that tight perioperative glycemic control (target RBS <150 mg%; 8.33 mmol/l) is associated with decreased mortality, less infection and shorter stay after open cardiac procedures in adults. [3] The first strong evidence against the traditional concept of tolerating glucose levels as high as 200 mg/dl (11.1 mmol/l) came from the prospective randomized controlled study on intensive insulin therapy (IIT) in adult surgical patients in 2001. The Leuven study with tight BG control with insulin showed striking decrease in ICU mortality from 8.0% to 4.6%, an absolute risk-reduction (ARR) of 3.4%; and in-hospital mortality decrease from 10.9% to 7.2%, an ARR of 3.7%. [1] The dramatic 42% relative reduction in mortality in the surgical ICU when BG was normalized to 80-110 mg/dl (4.4 to 6.1 mmol/l) by insulin infusion led to the practice of reducing glucose levels in critically ill-patients as well as in all hospitalized patients. [44] However, when the new practice acquired in the wave of enthusiasm following the Leuven study was put to test, results were contradictory; two multicenter randomized European studies were prematurely discontinued due to an alarmingly high rate of hypoglycemia in the "TGC" arm with no mortality benefit, two additional single center randomized studies showed a trend toward a higher mortality in the "TGC" arm. [4],[45],[46],[47] Two meta-analyses on the subject reached disparate conclusions. [5],[48] Important methodological differences between these studies and the Leuven study were cited as the reasons for the conflicting results and it was argued, that the later studies were underpowered to detect a reasonable mortality difference. [49] Thus, to provide a definitive answer and to test the hypothesis that TGC reduces mortality, a randomized unblinded trial "NICE-SUGAR" including 6104 patients in the ICU was designed. [8] Study participants were randomly assigned to glucose control with one of two target ranges: The intensive control target of 81-108 mg/dl (4.5-6.0 mmol/l) or a conventional control target of 180 mg/dl or less (10.0 mmol or less/l). The results of NICE-SUGAR contrasted starkly with those of preceding trials, and showed an absolute increase in the mortality at 90 days with intensive glucose control when compared to conventional control (27.5% vs. 24.9%; P - 0.02). Severe hypoglycemia, expectedly, occurred in more patients in the intensive control group than in the conventional control group (6.8% vs. 0.5%; P < 0.001). Investigators concluded that a BG target of <180 mg/dl (9.99 mmol/l) lowered mortality than a target of 81-108 mg/dl (4.49-5.99 mmol/l). Unfortunately, it is not understood why a TGC should "increase" mortality. The answer awaits further studies. Before attempting to infer conclusively, the differences between the Leuven and NICE-SUGAR trial should be considered as elaborated in a recent article from the Leuven group. [49] First, in NICE-SUGAR trial normoglycemia was compared with control targets of 140-180 mg/dl (8-10 mmol/l) whereas in Leuven study normoglycemia was compared with a control target of 180-215 mg/dl (10-12 mmol/l), making the comparison of the two studies very difficult. In addition, the other methodological differences including different blood sampling sites, glucose measurement tool, insulin infusion routes and nutritional strategies potentially confound the comparison. Notwithstanding the variables, the disturbing fact remains that whereas TGC lowered the mortality by absolute 3% in Leuven study, similar attempts increased it by absolute 3% in NICE-SUGAR trial. Equally important is the fact that by design the NICE-SUGAR trial is substantially more powerful than the Leuven study. The American Association of Clinical Endocrinologists and American Diabetes Association recommends insulin therapy in critically ill-patients, if BG levels exceed 180 mg/dl (9.99 mmol/l). [50] In view of persistently inconclusive and contradictory evidences and potentially serious repercussions of hypoglycemia, a routine policy of TGC (70-110 mg/dl; 3.88-6.11 mmol/l) seem to have limited value in the management of critically ill-patients. Pending definitive scientific evidence, it appears reasonable to maintain the BG concentration between a safe intermediate range of 140-180 mg/dl (7.77-9.99 mmol/l) or possibly better if maintained <150 mg/dl (8.3 mmol/l). [51]

Glycemic control in pediatric critical care

Hyperglycemia has been linked to worse outcomes in critically ill-children with trauma, sepsis and burns especially in neonates. Randomized controlled trials in pediatric intensive care unit (PICU) of Leuven University, Belgium, demonstrated beneficial response with tight sugar control. The trial was done with 700 infants and children who were randomly allocated to IIT group or conventional insulin therapy group (CIT). Target BG range in IIT group was 50-80 mg/dl (2.77-4.44 mmol/l) in infants and 70-100 mg/dl (3.88-5.55 mmol/l) in children of more than 1 year. In CIT group, insulin was administered to prevent RBS from exceeding the renal threshold of 180 mg/dl (9.99 mmol/l). Though IIT group had increased incidence of hypoglycemia (25% patients had more than one hypoglycemic event, RBS <40 mg/dl = 2.22 mmol/l) during PICU stay, better outcomes were also seen with same group, thus demonstrating need for glycemic control.

Glycemic control in pediatric cardiac surgical patients

The issue of glycemic control in pediatric patients is more complex. There are problems of cut-off values for defining hyperglycemia and hypoglycemia. The age-adjusted thresholds of normal fasting BG concentrations is 30-60 mg/dl (1.7-3.3 mmol/l) in neonates; 40-90 mg/dl (2.2-5.0 mmol/l) in infants; 60-100 mg/dl (3.3-5.5 mmol/l) in 2 nd year of life; and 70-106 mg/dl (3.9-5.9 mmol/l) in children beyond 2 years of age. [52],[53] There is uncertainty over the level and duration of hypoglycemia, the Achilles' heel of TGC that can cause damage. [54] Hypoglycemia results in dire consequences in the developing brain of neonates and infants [55],[56] and is directly associated with increased mortality and morbidity. [10] Children are more susceptible to develop hypoglycemia due to limited glycogen reserves. The speculation fuelled by adverse result of NICE-SUGAR trial, that insulin therapy may itself have fatal consequence, further dampens the enthusiasm to treat hyperglycemia aggressively. In 2009, Vlasselaers et al. in a randomized blinded clinical trial described the effects of glycemic control in the pediatric population [57] - a reduction in the inflammatory marker, C-reactive protein and duration of ICU stay were the primary outcomes. Infants were treated to a target blood sugar 50-79 mg/dl (2.8-4.4 mmol/l) and in children the targeted blood sugar was 70-100 mg/dl (3.9-l5.6 mmol/l) with insulin infusion administered throughout PICU stay or insulin was infused only to prevent BG from exceeding 214.41 mg/dl (11.9 mmol/l). Both end-points showed a statistically significant reduction in the treatment group (700 critically ill-patients; 317 infants <1 year and 383 children 1 year or more); the secondary outcomes, rate of infections and death, also improved. This proof-of-concept study needs further validation. In 2010, the Leuven group undertook a prospective randomized study of the glycemic control in neonates to show that TGC-target BG at 50-80 mg/dl (2.78-4.44 mmol/l) vis-a-vis 180-215 mg/dl (9.99-11.93 mmol/l) significantly reduced circulating levels of cardiac troponin-I, heart fatty-acid-binding protein, B-type natriuretic peptide and the need for vasoactive support. [58] Further, TGC suppressed the rise of proinflammatory cytokines, interleukin-6, 8 and C-reactive protein. The authors concluded that in neonates undergoing cardiac surgery TGC protects the myocardium and reduces inflammatory response. Hypoglycemia, defined as a BG level <30 mg/dl (1.67 mmol/l) occurred in nearly third (28%) of the cases in TGC group. Given its very small sample size (14 patients in each group), and, occurrence of high hypoglycemic events, that too in a highly familiar set-up, precludes any definitive inference. It should be noted that in this study, in the control group, hyperglycemia was only treated when BG exceeded 215 mg/dl (11.93 mmol/l) on two occasions and insulin was stopped when BG decreased below 180 mg/dl (9.99 mmol/l). As of now, there are not enough robust evidences to support a policy of TGC in pediatric group. Therefore, given the potentially fatal consequences of hypoglycemia, accepting a moderate hyperglycemia of around 140 mg/dl (7.7 mmol/l) appears a safer approach. In a two center prospective randomized trial (Boston Children's Hospital and Harvard Medical School, Boston, USA), [11] 980 children (aged 0-36 months) undergoing cardiac surgery under CPB, were enrolled and randomly assigned to have a blood sugar value of 80-110 mg/dl (4.4-6.1 mmol/l) or standard care in cardiac ICU. In TGC children 444 of 490 (91%) received insulin whereas only (2%) 9 of 490 received insulin infusion in children assigned to standard care. TGC was not associated with a significant decrease in infections (8.6 vs. 9.9/1000 patient days, P- 0.67). Mortality, length of stay, organ failure and hypoglycemia (blood sugar <40 mg/dl; 2.2 mmol/l) did not differ significantly.

Continuous glucose monitoring (CGM) is a safety feature against hypoglycemia when TGC is aimed. [59] Perhaps, the undetected hypoglycemia may be the reason for increased adverse outcomes in non-Leuven study. An in silico study [60] into the potential of CGM device to reduce clinical effort in TGC was done. It used retrospective data from specialized relative insulin nutrition titration (SPRINT) TGC study covering 20 patients from benchmark cohort. Clinically validated metabolic system models were used to generate BG profile for each patient resulting in 33 continuous separate BG episodes (6881 patient h). In silico analysis was performed with three different stochastic noise models- two Gaussian and one first order autoregressive. The noisy, virtual CGM BG values are filtered and used to drive SPRINT TGC protocol. A threshold alarm is used to trigger glucose interventions to avert hypoglycemia. The study found CGMs even with significant noise have no significant clinical impact on TGC performance or interventions if relatively simple and common filters are used. Glucose bolus size is critical. The study found approximately 12.5 g to be relatively optimal and boluses of 25-40 g can counter-intuitively raise hypoglycemia as the controller seeks to adjust to sudden BG change. According to study, the use of CGMs in SPRINT should reduce average nursing burden for measurement up to 75% saving approximately 25-30 min/patient/day, which is meaningful in a very busy ICU.

What the future holds?

Prompt recognition of hyperglycemia and its immediate control by insulin paves way for smoother convalescence. As cardiac surgical interventions witness continued decrease in the absolute risk, the thrust of management would be on reducing the morbidity related to such interventions. Glycemic control is certain to bring itself to the fore given its unquestionable links with the pathophysiology of convalescence. It will definitely continue to intrigue us that why such disparate results were generated from the "Leuven" and "other-than-Leuven" groups. One hopes that the future is pregnant with definitive evidence.

Hypoglycemia, owing to its association with increased morbidity and mortality is considered harmful. Pending definitive scientific evidence, it appears reasonable to maintain blood sugar level between a safe intermediate range of 140-180 mg/dl (7.77-9.99 mmol/l) or better still at <150 mg/dl (8.33 mmol/l) keeping in view the potentially dangerous consequences of hypoglycemia and hyperglycemia.